CN112741806A - Sustained and controlled release drug delivery system for senile dementia - Google Patents

Abstract

The invention relates to a sustained and controlled release drug delivery system for senile dementia, belonging to the technical field of pharmaceutical preparations. The present invention includes a first composition comprising a drug and carboxymethyl cellulose, and a second composition comprising carboxymethyl cellulose, the carboxymethyl cellulose in the second composition having a higher molecular weight than the carboxymethyl cellulose in the first composition. The first composition and the second composition cooperate to release the maximum dose of the drug with a minimum of residual drug remaining in the formulation, and it is another object of the present invention to provide a pharmaceutical dosage form for in vivo release treatment of senile dementia, which can obtain good therapeutic effect by using two different polymers to be released from the device.

Description

Sustained and controlled release drug delivery system for senile dementia

Technical Field

The invention relates to a sustained and controlled release drug delivery system for senile dementia, belonging to the technical field of pharmaceutical preparations.

Background

Controlled release dosage forms are becoming increasingly important because of the good therapeutic effect obtained when delivering drugs to animals. The controlled release of drug from the dosage form is shown to control the duration and release profile of drug release. Controlled release dosage forms have a number of therapeutic advantages over conventional dosage forms. For example, one major and important advantage is the reduction of fluctuations in blood drug levels. The pharmacological basis for reducing fluctuations in blood drug levels comes from the following three principles. First, each drug must achieve a drug plasma level at which it is effective if the desired therapeutic effect is to be obtained from the drug. Second, most drugs have an upper limit on their blood levels or side effects may occur, which can be substantially avoided by using controlled release dosage forms. Third, the blood level of most drugs is directly proportional to the administered concentration, indicating the need for a controlled release dosage form. These pharmacological principles indicate that blood drug levels need to be maintained within therapeutic levels, thus satisfying the need for controlled release dosage forms to achieve the desired results.

Dosage forms for drug administration can influence the course of treatment by influencing the distribution of drug concentration in the blood. For example, following administration by conventional dosage forms of the prior art, the blood concentration profile of the drug initially peaks, which we define as the peak blood concentration, and then declines rapidly. The initial high peak of the drug over the slope and duration typically greatly exceeds the range of plasma drug concentrations required for treatment, and the peaks and troughs of plasma drug concentrations tend to be higher or lower than the plasma drug concentrations required for treatment. In contrast, the controlled-release formulation can minimize the known fluctuation even while avoiding the peak of blood concentration and the subsequent trough of blood concentration, as compared with the prior art. A single controlled release formulation can continue to provide therapeutic benefits over the entire treatment period.

In view of the above, there is an immediate and obvious urgent need for a controlled release formulation for administration of therapeutically important drugs to patients in need of treatment of senile dementia. Medicaments having these therapeutic properties and useful for treating senile dementia which can be administered by the formulations and methods of the present invention include donepezil, huperzine A, aricept, memantine, rivastigmine, galantamine, nimodipine, nicergoline, or a pharmaceutically acceptable salt or a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include alkyl substituted derivatives and ester derivatives. The acid may be an organic acid or an inorganic acid, and the salt may be an inorganic salt or an organic salt. The pharmaceutically acceptable salts of the present invention include components selected from the group consisting of inorganic salts, hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates and the like, and organic salts trifluoroacetates, trichloroacetates, acetates, glycolates, pyruvates, malonates, succinates, maleates, fumarates, malates, tartaric acid, citric acid, mandelic acid, benzoic acid, cinnamic acid, methane sulfonic acid, ethane sulfonic acid, salicylic acid, p-toluene sulfonic acid or cyclohexane sulfonic acid. Osmotic dosage forms manufactured for delivery of drugs to the environment of use were first disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899. The osmotic devices disclosed in these patents include a semipermeable membrane surrounding a drug-containing compartment. The semi-permeable membrane has a passageway that is permeable to external fluids and substantially impermeable to internal drugs. There is a passageway through the semi-permeable membrane for the release of the drug from the device. These devices enter the device by permeation through the semipermeable membrane by an external fluid at a permeation rate that is determined by the permeability of the semipermeable membrane. The inner and outer osmotic pressure gradient of the device pushes the medicine-containing aqueous solution in the device to be discharged outwards through the channel. These devices are effective for releasing drugs in aqueous solutions, but generally they do not completely release all of the drug present in this thixotropic pharmaceutical carrier.

A precursor technology for osmotic delivery devices is described in U.S. Pat. No.4,111,202. In this patent, the device enhances the kinetics of administration by manufacturing a device with drug compartments and osmotic agents to release drugs that are difficult to release in aqueous liquids due to solubility problems, e.g., very soluble or insoluble in water. A compartment separated by a diaphragm that is displaceable from a rest or substantially straight position to a curved position. The device exerts a driving force on the membrane by absorbing liquid into the osmotic agent compartment, thereby creating a solution that causes the volume of the compartment to increase. This force causes the membrane to expand towards the drug compartment and correspondingly reduces the volume of the compartment, whereby the drug diffuses out of the device through the channel. Although the device may be successfully used for its intended purpose and although it may release many difficult to deliver drugs, its use is limited due to the manufacturing steps required to manufacture and place the septum in the device.

U.S. Pat. No.4,327,725 provides an osmotic delivery device for delivering beneficial agents that have difficulty delivering therapeutic doses of the agents in large quantities at controlled rates over time due to their solubility in water and biological fluids. This patent includes a semi-permeable membrane surrounding a compartment containing a beneficial agent that is insoluble or readily soluble in water and biological fluids. The device also includes a swellable hydrogel. In operation, external fluid is drawn into the device, and the hydrogel swells in the presence of the external fluid and pushes the aqueous drug solution through the channels of the device. The device successfully achieves the intended use and is expected to be useful for many beneficial drugs that are difficult to deliver. However, it has been observed that hydrogels are often limited in their use because they currently do not absorb enough liquid to achieve the maximum amount of self-expansion needed to push all of the beneficial agent out of the device.

In U.S. Pat. Nos. 4,765,989 and 4,783,337, a novel delivery device is provided for delivering a drug to a patient in need of treatment. The delivery devices of these patents include a liquid permeable material membrane and liquid impermeable channels. An outlet in the substance membrane connects the drug in the compartment with the exterior of the delivery device. The device comprises first and second compositions comprising methylcellulose, a mixture of agar and carboxymethylcellulose or a mixture of hydroxypropyl methylcellulose and sodium carboxymethylcellulose. These patents do not teach the regulation and control of the ingredients used to completely release all of the drug, and the release rate behavior associated with the drug delivery device.

Those skilled in the art of drug delivery will recognize that such delivery devices would be of positive value if delivery devices were provided comprising different internal compositions that exhibit high levels of hydrodynamic and osmotic activity to release the drug at a controlled rate for treatment, representing an advancement in drug delivery technology. Likewise, those skilled in the art of dispensing will immediately recognize that such drug delivery devices would find practical application in medicine and pharmaceuticals if provided with thermodynamic activity for controlled dosage drug release. It has now been found that a device can be used to facilitate complete release of all of the above drugs from the device by using different hydrogel polymers to provide maximum self-release of the drug and maximum self-swelling of the polymer.

Disclosure of Invention

Accordingly, in view of the above, it is a direct object of the present invention to provide a dosage form that is formulated as a drug delivery device to provide an advance over the prior art.

It is another object of the present invention to provide a dosage form made as a release device comprising a first composition and a different second composition for releasing substantially all of the drug over time.

It is another object of the present invention to provide a dosage form comprising a first composition comprising a drug and a selected cellulosic polymer and a second composition comprising a selected cellulosic polymer different from the polymer in the first composition to improve the drug release characteristics of the dosage form.

It is another object of the present invention to provide a dosage form comprising two separate compositions, each composition comprising a polymer of different molecular weight, for releasing the drug at a controlled rate over an extended period of 30 minutes to 72 hours.

The dosage form includes a first composition comprising a drug and carboxymethyl cellulose, and a second composition comprising carboxymethyl cellulose, the carboxymethyl cellulose in the second composition having a higher molecular weight than the carboxymethyl cellulose in the first composition. The first and second compositions cooperate to release the maximum dose of drug, while minimizing residual drug remaining in the formulation,

it is another object of the present invention to provide a pharmaceutical dosage form for in vivo release for treatment of senile dementia, which can obtain good therapeutic effect by using two different polymers to be released from the device.

It is another object of the present invention to provide a formulation comprising an osmotic structure having two compositions that function as an integral unit, the formulation including a first osmotic composition comprising a drug and an osmopolymer, and a second composition comprising a different osmopolymer, the first and second compositions cooperating to hydrodynamically and osmotically release the drug from the dosage form.

It is another object of the present invention to provide an osmotic formulation having a high loading of a water-soluble or water-insoluble therapeutic drug for senile dementia from 10ng to 800 mg for releasing the drug by interacting with two compositions comprising different polymers. The drug is released continuously at a controlled rate.

It is another object of the present invention to provide an osmotic formulation that includes a first composition including an osmopolymer that produces a unique osmotic activity independently of the other osmopolymers, but which releases drug from the device in a synergistic effect, and a second composition including a different osmopolymer.

It is another object of the present invention to provide an osmotic formulation that is completely administered, releases drug continuously at a controlled rate and over a given period of time, using a treatment that requires intervention to initiate the treatment regimen and possibly terminate it in this manner.

It is another object of the present invention to provide an osmotic formulation which can contain a therapeutic drug for senile dementia and, after oral administration, release the drug to the gastrointestinal tract at a small dose per hour at an average rate throughout the gastrointestinal tract.

It is another object of the present invention to provide an osmotic formulation having a compartment including a first polymer component and a second different polymer component therein, the first polymer component and the second different polymer component simultaneously maintaining their original characteristics and function as a unitary body for releasing a drug from the formulation.

It is another object of the present invention to provide a dosage form that includes an osmopolymer made without radiation, such as gamma radiation, thereby eliminating any potential source of risk or radiation to the dosage form and patient.

It is another object of the present invention to provide a poly (alkylene oxide) -free dosage form for administering a drug to a patient in need of controlled drug therapy. It is another object of the present invention to provide an osmotic formulation that includes a non-radiative osmotic polymer to enhance patient and physician acceptance of the dosage form.

Drawings

Fig. 1 is a view of an osmotic agent sized, shaped, and adapted for oral administration into the gastrointestinal tract of a patient in need of drug treatment, with a portion of the outer membrane of the agent removed to illustrate the structure of the dosage form.

Fig. 2 is a cross-sectional view of the osmotic formulation of the drawing.

Fig. 3 is a graph depicting the cumulative amount of drug released by the formulation over time.

Detailed Description

In the drawings and specification, like parts are designated by like parts in the relevant drawings. Terms appearing earlier in the description of the specification and drawings, and in embodiments thereof, are further detailed elsewhere in this disclosure.

Detailed description of the drawingsthe accompanying drawings, which are, and should not be considered as limiting, an example of a dosage form provided by the present invention, are now described in detail, with reference to the accompanying drawings, in which an example of an osmotic formulation is illustrated, in fig. 1 and in fig. 2.

In fig. 1, the entire osmotic formulation is represented by the numeral 10. 10 includes a body member 11, the body member 11 including a substance film 12 enclosing an internal compartment, which is not visible in fig. 1. The formulation 10 includes at least one passageway 13 that connects the interior of the dosage form 10 with the external biological environment of use.

In fig. 2, the osmotic formulation 10 is opened and the internal structure of the formulation 10 is seen at 14. As shown, the formulation 10 includes a body 11 and a substance film 12. The substance membrane 12 surrounds, forms and encloses the interior compartment 15. The substance membrane 12 includes one channel 13, or alternatively, more than one exit channel, for releasing the drug 16 (indicated by dots). Drug 16 is released from compartment 15 of dosage form 10. Drug 16, as defined herein, includes any drug that can be released from formulation 10 to produce a therapeutically useful result for a patient. In the present application, the term "drug" includes any physiologically or pharmacologically active substance that produces a local or systemic effect in an animal, including a warm-blooded mammal, including a human. The drug that may be released by the formulation 10 includes drugs that are insoluble or highly soluble in body fluids including aqueous organisms. In a presently preferred embodiment, the drug 16 comprises a senile dementia drug. The substance membrane 12 of the formulation 10 is permeable to external liquids present in the biological environment of use and is substantially impermeable to the drug 16, its salts or derivatives thereof and other components therein in the compartment 15. The substance membrane 12 is substantially inert, non-toxic, and maintains its physical and chemical integrity during drug release of the formulation 10. The phrase "maintaining its physical and chemical integrity" means that the substance membrane 12 does not lose its physical structure throughout the release of the drug from the formulation 10. In one presently preferred embodiment, the material film 12 comprises a member selected from the group consisting of cellulose esters, cellulose ethers, or cellulose ester-ethers. In a more preferred embodiment, the substance film 12 comprises a member selected from the group consisting of: cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate. The cellulose polymer member constituting the substance film 12 includes cellulose acetate having a degree of substitution of at most 1 and an acetyl content of at most 21%, cellulose diacetate having a degree of substitution of 1 to 2 and an acetyl content of 21% to 35%, and cellulose triacetate having a degree of substitution of 2 to 3 and an acetyl content of 35% to 44%. The amount of cellulosic polymer present in the material film 12 of the formulation 10 is from 85% to 100% (by weight). The substance membrane 12 optionally includes a glidant, such as polyethylene glycol, to help regulate liquid flux through the semipermeable substance membrane 12. The flux enhancer polyethylene glycol has a molecular weight in the range of 1500 to 7500. The concentration of polyethylene glycol in the substance membrane 12 optionally comprises a total concentration of the components of the substance membrane of 1% to 15% (by weight), the total concentration of the components constituting the substance membrane 12 being equal to 100%.

The compartment 15, in the pharmaceutical composition, also defined as first composition, comprises 20% to 98% (by weight) of a basic carboxymethyl cellulose ether 17, indicated by wavy lines, mixed with the drug 16. The present invention has unexpectedly found carboxymethyl cellulose ether 17. Or a non-toxic alkali metal salt thereof, may be used as a delivery vehicle for drug 16. The amount of drug 16 present in compartment 15 is between 2% and 45%. The carboxymethyl cellulose ether 17 comprises sodium or potassium carboxymethyl cellulose and has an initial gel flow resistance strength. Carboxymethyl cellulose 17 containing drug 16 converts to a diffusible thixotropic aqueous drug formulation upon contact with an aqueous liquid absorbed into formulation 10. This diffusible drug composition exerts a shear stress on the formulation in the presence of a separate osmotic-push force generated in the formulation 10, causing the drug to be pushed through the outlet 13 within 24 hours. Basic carboxymethylcellulose 17 useful for driving drug 16 has a degree of polymerization of 20 to 1,200, a molecular weight of 10,000 to 300,000, and a viscosity of 25 to 1750 cps in a 2% aqueous solution at 25 ℃. Preferably, the pharmaceutical preparation in manufacture comprises 0-40% polyvinylpyrrolidone 18, indicated by the vertical line and comprising a molecular weight of 15000-75000, 0-40% hydroxypropylcellulose 19, indicated by the diagonal line, comprising a molecular weight of 20000-80000 and 0-5% of a lubricant, such as magnesium stearate, calcium stearate or stearic acid, which comprises the pharmaceutical preparation or all the constituents of the first component in a weight amount equal to 100%.

A propellant 20 is included in compartment 15 of dosage form 10. Propellant 20 is also defined as the second composition, and when dosage form 10 is in operation, propellant 20 absorbs liquid, expands, and then pushes the pharmaceutical composition through outlet 13 of formulation 10. Propellant 20 comprises 6.5% to 100% of carboxymethyl cellulose 21 having a molecular weight of greater than 300,000 to 1,200,000 and a degree of polymerization of greater than 1200 to 4,500. The propellant in the preferred manufacture comprises 0% to 25% of an osmotic agent 22 represented by a circle selected from an osmotically active salt, an osmotically active carbohydrate, an osmotically active polysaccharide, an osmotically active oxide or an osmotically active acid solute. 0% to 25% of hydroxypropylmethylcellulose 23, represented by a square, comprising a molecular weight of 9200 to 20000, and from 0% to 5% of a lubricant comprising magnesium, stearic or calcium stearate, and 0 to 3% of iron oxide, the weight of all the ingredients in the propellant being equal to 100%.

The expression "outlet channel 13" includes devices and methods suitable for dispensing a beneficial agent 16 from the formulation 10. The outlet means comprises one or more channels passing through the substance membrane 12 for communicating the drug 16 in the compartment 15. The expression "a channel" includes a slit, a port, a chisel, a hole, a porous element through which the purpose of diffusing the drug 16 is achieved, and the form may be composed of a hollow fiber, a capillary, a microporous insert or a micropore. Thus, a partially microporous substance membrane is optional in the present invention. The expression includes a material which is eroded or leached from the substance film 12 in the body fluid environment in which it is used, to produce one or more drug release channels of controlled size. Representative materials suitable for forming at least one channel, two channels or more include leachable materials comprising an erodible polyglycolic or polylactic acid member in the film of the material, a gelatinous filament, polyvinyl alcohol, such as a removable liquid pore former, providing an exit orifice with release rate controlling properties. The channel or channels may be formed by leaching a material such as sorbitol, mannitol or sodium chloride from the substance membrane. The channels may have any shape, such as circular, triangular, square, oval or irregular. Dosage forms of the formulations may be constructed in spaced apart relation or with one or more channels on a single surface or on more surfaces of a formulation.

Formulation 10 was made by standard manufacturing methods. For example, in one method of manufacture, the drug and other ingredients comprising the drug formulation are uniformly mixed and compressed into a solid formulation. The compressed formulation has dimensions corresponding to the internal dimensions of the area occupied by the drug formulation in formulation 10. The formulation also corresponds to the size of the propellant with which it comes into contact. In this manufacturing process, the drug and other ingredients comprising the ingredients are mixed with a solvent and mixed into a solid or semi-solid form by conventional methods such as ball milling, calendaring, stirring or rolling, and then pressed into a predetermined shape. Next, the propellant composition is contacted with the pharmaceutical composition. The pharmaceutical compositions, propellant compositions, may be compressed by using a conventional bi-layer tablet press. The pharmaceutical composition and propellant composition are coated with a semipermeable membrane material. The semipermeable membrane may be coated by compression coating, molding, spraying, dipping or coating procedures. The compressed pharmaceutical composition and propellant composition are suspended and tumbled in an air stream containing a film-forming material for coating. The dosage forms provided by the present invention may include a variety of shapes for administration. The dosage form may be, for example, round, square, oval, bean-shaped or caplet-shaped. The dosage form can be made into sublingual preparation, buccal preparation or gastrointestinal preparation.

In another method of manufacture, formulation 10 is manufactured by a wet granulation technique. In the wet granulation technique, the drug and the ingredients comprising the pharmaceutical composition are mixed using an organic co-solvent such as isopropanol-dichloromethane 80/20 v/v (volume/volume) as a wetting agent. The ingredients forming the pharmaceutical composition were passed through a 40 mesh screen and mixed thoroughly in a mixer. Other optional ingredients comprising the pharmaceutical composition are dissolved in a portion of the humectant and added to the pharmaceutical mixture under continuous mixing with a stirrer. The remaining humectant was added until a soft mass was produced, and then the wet soft mass was pressed through a 20 mesh screen onto the baking pan of the oven. The damp mass was dried in an oven at 50 ℃ for 18 to 24 hours. The dried granules were then sized through a 20 mesh screen. Next, a lubricant such as magnesium stearate that has passed through an 80 mesh screen is added to the screened drug particles and mixed in a V-blender for 5 to 10 minutes. The composition is compressed into tablets, for example, in a 3-position manesty. The tablet press speed was set at 30 rpm and the maximum pressure was set at 2 tons. The medicament is laminated to the propellant composition and the bilayer medicament-propellant tablet cores are then fed to a coating machine.

Another method of manufacturing a pharmaceutical composition-propellant composition comprises separately mixing powdered ingredients comprising the pharmaceutical composition or the propellant composition in a fluid bed granulator. After dry blending the powdered ingredients in a granulator, a binder (e.g., an aqueous solution of polyvinylpyrrolidone) is sprayed onto the powder. The coated powder is then dried in a granulator. This process granulates all the ingredients present therein while adding a binder. After the granules are dried, a lubricant, such as stearic acid or magnesium stearate, is added to the granules in a V-blender and mixed for 5 to 10 minutes. The granules were then compressed in the manner described above.

The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention in any way.

Example 1

An osmotic formulation for controlled and sustained release of memantine prepared by the method comprising: 200 g of memantine, 300 g of hydroxypropyl cellulose with a molecular weight of 60,000, 295 g of sodium carboxymethyl cellulose with a molecular weight of 90,000 and 100g of polyvinylpyrrolidone with a molecular weight of 40,000 were mixed and then sieved through a 40 mesh. The sieved composition was then placed into a Glatt fluid bed granulator, mixed and slightly heated to 35 ℃ to produce a homogeneous mixed powder. Next, a binder consisting of 100g of polyvinylpyrrolidone (400 ml of purified water having a molecular weight of 40000) was sprayed onto the fluidized powder.

After the spraying cycle is started, the process is monitored to ensure uniformity. The particles were dried in situ and sieved through a 16 mesh screen. Next, 5g of magnesium stearate was sieved through an 80 mesh screen, added to the granules in the mixer, and mixed to a homogeneous composition. The composition produced by this process comprises 20% memantine, 30% hydroxypropyl cellulose, 29.5% sodium carboxymethyl cellulose, 20% polyvinylpyrrolidone and 0.5% magnesium stearate. The composition is divided into pharmaceutical formulations for the preparation of a formulation comprising 60mg of memantine, 90mg of hydroxypropyl cellulose, 88.5mg of sodium carboxymethyl cellulose, 60mg of polyvinylpyrrolidone and 1.5mg of magnesium stearate.

Next, a propellant was prepared in the same manner. First, 788 g of sodium carboxymethylcellulose having a molecular weight of 700,000, 10 g of iron oxide and 50g of polyvinylpyrrolidone having a molecular weight of 40,000 were sieved through a 40-mesh sieve, and then 100g of sodium chloride was sieved through a 60-mesh sieve. The two screened materials were mixed and heated to 30 ℃ in a fluid bed granulator. Next, a granulation solution containing 50g of polyvinylpyrrolidone of 40,000 molecular weight in 400 ml of distilled water was sprayed onto the granules. Next, the granules were mixed and added to a fluid bed granulator. 50g of a binder of a 40,000 molecular weight aqueous solution of polyvinylpyrrolidone were coated on the granules prepared in the fluidized bed. The particles were then dried in situ and sieved through a 16 mesh screen. Two grams of magnesium stearate were then screened through an 80 mesh screen and added to the granules in a blender and mixed for 7 minutes at moderate mixing speed. The composition formed by this process contained 78.8% sodium carboxymethylcellulose containing a molecular weight of 700,000, 10% sodium chloride, 10% polyvinylpyrrolidone containing a molecular weight of 40,000, 1.0% ferric oxide and 0.2% magnesium stearate. The same composition was divided into propellant compositions for forming the second composition of the formulation, which had the following mass in mg: 118.2mg contains 700,000 molecules of sodium carboxymethyl cellulose, 15mg of sodium chloride, 15mg of polyvinylpyrrolidone having 40,000 molecules by weight 1.5mg of iron oxide and 0.3mg of magnesium stearate.

Next, the drug composition and propellant composition are fed into a bi-layer tablet press and compressed into bi-layer tablet cores. The bilayer tablet cores were then coated with a coating machine of a substance film-forming composition comprising 90% cellulose acetate having an acetyl content of 39.8% and 10% polyethylene glycol having a molecular weight of 3350 dissolved in 90% dichloromethane and 10% methanol solution. Then, a 25mil (0.650 mm) hole was laser drilled in the center of the film of material facing the drug side. Next, the entire delivery device was dried in an oven to remove residual solvent. These tablets are coated with an inert coating material to improve appearance.

The drug delivery system provided by the invention uses carboxymethyl cellulose in the pharmaceutical composition. And another and higher molecular weight carboxymethylcellulose is used in the propellant composition. The use of two different molecular weight carboxymethyl cellulose polymers provides unexpected results compared to the prior art. The composition prepared according to this patent, which comprises a drug and a polymer having a molecular weight of 200,000, results in a residual drug concentration in the dosage form of more than 11%. Also, the dosage form provided by this technique, which contains the drug and 300,000 molecular weight polymer, leaves a residual concentration of drug in the dosage form of 15%. The present invention has unexpectedly found that a dosage form comprising two different molecular weight carboxymethylcellulose and a higher molecular weight carboxymethylcellulose in the propellant exhibits as low as 3.5% residual drug in the dosage form at the end of the drug release period. The improvement in drug release of the present invention is unexpected and it significantly enhances the utility of the present dosage form for improved drug therapy. With the present dosage form, both the physician and the patient know that the patient is substantially receiving the intended therapeutic dose of the drug for drug therapy. Description of the drawings 3 shows the total concentration of drug released over time, for example memantine.

Example 2

The formulation for administering a drug to a patient according to claim 1, wherein the formulation comprises an amount of an oral drug having a molecular weight of 10,000 to 300,000, hydroxypropyl cellulose, polyvinylpyrrolidone, and carboxymethyl cellulose.

Example 3

A formulation for the delivery of a drug to a patient according to claim 1, wherein the formulation comprises a dose of memantine, hydroxypropylcellulose, polyvinylpyrrolidone and carboxymethylcellulose having a molecular weight of 10,000 to 300,000.

Example 4

The dosage form for oral administration to a patient according to claim 1, wherein the drug is selected from donepezil, huperzine A, aricept, memantine, rivastigmine, galantamine, nimodipine, nicergoline.

Example 5

The formulation of galantamine was prepared as follows: first, 9.40kg of galantamine, 0.20kg of sodium carboxymethylcellulose having a molecular weight of 200,000, and 0.10kg of hydroxypropyl cellulose having a molecular weight of 30,000 were added to a blender and mixed for 15 minutes to produce uniform mixing. Next, 0.20kg of polyvinylpyrrolidone having a molecular weight of 38,000 was mixed with 350ml of anhydrous ethanol to form an adhesive. The binder is then slowly added to the mixed ingredients, and then all the ingredients are mixed to produce a wet mass. The wet mass was dried in an oven at room temperature of about 25 ℃ for 17 to 23 hours to evaporate the ethanol. The dried granules were then dried at 50 ℃ for an additional 2-4 hours. The dried granules were then passed through a 30 mesh screen. Next, 0.10kg of lubricant magnesium stearate was added to the drug mixture and blended for 9 minutes to produce a homogeneous composition.

Next, a propellant composition was prepared as follows: first, 4.35kg of sodium carboxymethylcellulose having a molecular weight of 65 ten thousand, 0.35kg of sodium chloride and 0.25kg of hydroxypropylmethylcellulose having a molecular weight of 11200 were mixed for 10 minutes to produce a uniform blend. Next, 350ml of denatured anhydrous ethanol was added as a wetting agent to produce a wet mass. Next, the granulated wet material was passed through a 30 mesh screen to form wet granules. The wet granulation is then spread onto a tray and dried at room temperature of 25 ℃ for 20 to 25 hours. The dried granules were then passed through a 20 mesh screen. The propellant composition is now ready for use in the manufacture of the final device.

Transferring the particles comprising galantamine to a first feed inlet of the hopper and feeding the particles comprising the push composition to a second feed inlet of the hopper. The feed hopper was placed on a bi-layer tablet press and the galantamine composition and propellant composition were compressed into tablets.

Next, the compressed composition is wrapped with a semipermeable membrane. The semipermeable membrane composition material is prepared as follows: first, a co-solvent was prepared by mixing 80 parts of methylene chloride with 20 parts of methanol (wt/wt), and cellulose acetate having an acetyl group content of 39.8% was slowly added thereto. Polyethylene glycol having a molecular weight of 3350 was then added to the freshly prepared ingredients. The compressed bi-layer tablets are then placed in a coating machine and coated.

Next, the coated tablets were removed from the coating machine and a 24mil (0.6 mm) hole was laser drilled in the semi-permeable membrane. The formulation was dried in a humidity oven at 50 c and 50% relative humidity for 48 hours to remove residual solvent from the semipermeable membrane. The formulation is sized and shaped for oral entry into the human gastrointestinal tract. The manufacturer provides a controlled release dosage form containing a 360 mg dose of galantamine, which can be extended to 24 hours.

Example 6

The above procedure is followed in this example to provide: (a) a sustained release oral osmotic pump tablet comprising 40mg, 80mg, 120mg, 240mg, or 480mg of a pharmaceutically acceptable salt of nicergoline; (b) sustained release oral osmotic pump tablets containing 30 mg, 60mg, 90mg, 120mg, 240mg or 480mg of a pharmaceutically acceptable salt of galantamine; or (c) a sustained release oral osmotic pump tablet comprising 20mg, 30 mg, 45 mg, 60mg, 90mg, or 120mg of memantine for relaxing and preventing coronary spasm, reducing oxygen demand, and reducing arterial blood pressure.

Example 7

The above procedure was followed in this example to prepare a formulation wherein the pharmaceutical composition comprised the drug memantine, polyvinylpyrrolidone, sodium carboxymethylcellulose with a molecular weight of 70,000, sodium lauryl sulfate and hydroxypropyl cellulose.

Example 8

In this example, following the above procedure, 0.1% to 15% of vitamin B is added_2。Also known as riboflavin, is mixed and used with memantine to impart protection against the adverse effects of light on memantine, and also to blend surfactants with memantine to enhance the fluid distribution characteristics of the pharmaceutical formulation in the dosage form. Surfactants useful for the intended purpose consist of members selected from the group consisting of anionic, cationic and nonionic surfactants,for example Pluronics, Cremophors, polyoxyalkylene fatty acid esters, polyoxyalkylene fatty acid ethers and alkoxylated hydrogenations, castor oil. The surfactant is present in a concentration of 0.01% to 15%, the total concentration of all ingredients in the formulation being equal to 100%.

Method for carrying out the invention

The present example relates to a method of delivering a drug to a human patient in need of treatment, the method comprising:

(A) an oral dosage form for delivery to the human body, the dosage form comprising:

(1) a substance membrane at least partially comprising a semipermeable composition, said substance membrane surrounding, defining and enclosing a compartment comprising:

a) a pharmaceutical composition comprising 10ng to 750mg of a drug, 20 to 98% of 10,000 to 300,000 molecular weight carboxymethyl cellulose, 0 to 40% of 15,000 to 75,000 molecular weight hydroxypropyl cellulose, 0 to 40% of 20,000 to 40,000 molecular weight polyvinylpyrrolidone and 0 to 5% of a lubricant;

(b) a propellant composition comprising 65% to 100% of a carboxymethyl cellulose having a molecular weight greater than 300,000 to 1,200,000, and 0 to 25% of an osmotic agent, and 0 to 25% of polyvinylpyrrolidone comprising a molecular weight of 20,000 to 40,000;

(2) a channel on the substance membrane for delivering the drug from the device;

(B) therapeutic purposes are achieved by absorbing body fluid from the patient into the compartment to form a releasable pharmaceutical composition and releasing the drug through the channel by expansion of the propellant composition.

In summary, it will be appreciated that the present invention lends itself to an unknown formulation form having practical medical utility in the field of drug delivery. While the invention has been described and pointed out in detail with reference to the operating embodiments thereof, it will be understood that various changes, modifications, substitutions and omissions may be made by those skilled in the art without departing from the spirit of the invention. Accordingly, it is intended that the patent protect equivalents of those elements included within the scope of the claims.

Claims (7)

1. A sustained-release drug delivery system for senile dementia, comprising:

(a) an oral dosage form for entry into a patient, the dosage form comprising:

(1) a first layer comprising 10ng to 750mg of a drug;

(3) a material membrane surrounding the first and second layers, the material membrane comprising at least a portion that is permeable to the passage of a fluid;

(4) an outlet channel in the substance membrane for delivering the drug from the dosage form to a patient; and wherein the one or more of the one,

(5) the first layer comprises a basic carboxymethyl cellulose having a molecular weight of 10,000 to 300,000; and wherein the first and second end portions of the first and,

(6) the second layer comprises a basic carboxymethyl cellulose having a molecular weight greater than 300,000; and wherein the dosage form of the formulation, when in use, is characterized by:

(7) a first layer, initially non-flowable, which becomes a diffusible drug-containing solution layer upon absorption of liquid;

(8) the second layer pushes the first layer through the outlet channel, wherein each alkali metal carboxymethyl cellulose retains its original independent character and function; thereby, (b) co-administering through the first and second layers to administer substantially all of the drug to the patient over time.

2. A method of administering to the gastrointestinal tract of senile dementia comprising:

(a) an oral dosage form for entry into a patient, the dosage form comprising:

(1) a first composition comprising 10ng to 750mg of a drug selected from donepezil, huperzine a, aricept, memantine, rivastigmine, galantamine, nimodipine, nicergoline;

(2) extruding the first composition out of a second composition of the formulation;

(3) a membrane of matter surrounding the first and second compositions, the membrane of matter at least partially comprising a fluid-permeable composition;

(4) an exit channel in the substance membrane for pushing the drug out of the dosage form for release to a patient; and wherein the one or more of the one,

(5) the first composition comprises a compound selected from potassium carboxymethyl cellulose and sodium carboxymethyl cellulose having a molecular weight of 10,000 to 300,000; and wherein the first and second end portions of the first and,

(6) a second composition comprising a compound selected from the group consisting of potassium carboxymethylcellulose having a molecular weight greater than 300,000 and sodium carboxymethylcellulose; and the combination of (a) and (b),

(b) co-administration of the first and second compositions is carried out to release substantially all of the drug to the patient over time.

3. The method of gastrointestinal administration of claim 2, wherein: the drug is replaced by another drug selected from donepezil, huperzine A, Arrissin, memantine, rivastigmine, galantamine, nimodipine, and nicergoline.

4. The sustained-release drug delivery system for senile dementia according to claim 1, wherein: the medicine can be used for treating senile dementia.

5. The method of claim 1, wherein the first composition comprises sodium lauryl sulfate.

6. The sustained-release drug delivery system for senile dementia according to claim 1, wherein: the channels are pores formed by etching a component of the material film to control the release rate.

7. The sustained-release drug delivery system for senile dementia according to claim 1, wherein: the channel is formed by laser drilling the material film.

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